β- Lactam Antibiotics

These are antibiotics having a beta-lactam ring. The two major groups are
penicillins and cephalosporins. Newer groups are Monobactams and
carbapenems.

(1) Thiazolidine ring; (2) beta-lactam ring; (X) Bond which is broken by penicillinase (a
beta-lactamase)
 PENICILLINS

Penicillin was the first antibiotic to be used clinically in 1941 Penicillin was

originally obtained from the fungus Penicillium notatum, but the present

source is a high yielding mutant of P. chysogenum.

Classification
Mechanism of
action
 WHY penicillin is non toxic to humans ?

The peptidoglycan cell wall is unique to bacteria.

No such substance is synthesized (particularly, D-
alanine is not utilized) by higher animals.
WHY penicillin is more toxic to gram (+) as compared to
gram (-)?

In gram (+) bacteria the cell wall is almost entirely made of peptidoglycan,
which is >50 layers thick and extensively cross linked, so that it may be regarded
as a single giant mucopeptide molecule.

In gram-negative bacteria, the cell wall consists of alternating layers of

lipoprotein and peptidoglycan (each layer 1- 2 molecule thick with little cross
linking).
Uses
Penicillin G is the drug of choice for infections caused by organisms susceptible to
it, unless the patient is allergic to this antibiotic.

I. Streptococcal infections Like pharyngitis, otitis media, scarlet fever,

rheumatic fever respond to ordinary does of PnG. For subacute bacterial
endocarditis (SABE) caused by Strep. viridans or faecolis high doses (10- 20
MU i.v. daily)

2. Pneumococcal infections PnG is infrequently used now for pneumococcal

(lobar) pneumonia and meningitis, only if the strain is sensitive.
3. Meningococcal infections are still mostly responsive: meningitis and
other infections may be treated with intravenous injection of high doses of
PnG.

4. Gonorrhoea PnG has become unreliable for the treatment of

gonorrhoea.

5. Syphilis T pallidum has not shown any resistance and PnG is the drug of
choice. Early and latent syphilis is treated either with daily i.m. injection of
1.2 MU of procaine penicillin for 10 days
6. Leprospirosis: (Leptospira) PnG 1.5 MU injecte d i. v. 6 hourly for 7 days is
curative.
7. Diphtheria Antitoxin Therapy is of prime importance. Procaine penicillin 1-2
MU daily for 10 days may be used to prevent carrier state.
8. Tetanus and gas gangrene Antitoxin and other measures are more important;
PnG 6-12 MU/day is used to kill the causative organism and has adjuvant value.

9 Prophylactic uses
(a) Rheumatic fever: Low concentrations of penicillin prevent colonisation by
streptococci.
(b) Bacterial endocarditis: Dental extractions, endoscopies. catheteriazation,
etc. cause bacteremia PnG can afford protection. but amoxicillin is preferred
now.
Adverse effects
Penicillin G is one of the most nontoxic antibiotics; up to 20 MU has been injected
in a day without any organ toxicity.

Local irritancy and direct toxicity Pain at i.m . injection site, nausea on oral
ingestion and thrombophlebitis of injected vein are dose-related expressions
o f irritancy.
Toxicity to the brain may be manifested as mental confusion, muscular
twitchings, convulsions and coma, when very large doses (> 20 MU) are
injected i.v.; especially in patients with renal insufficiency.

Hypersensitivity An incidence of 1- 10% is reported. Individuals with an allergic

diathesis are more prone to develop penicillin reactions. Frequent manifestations
of penicillin allergy are-rash, itching, urticaria and fever. Wheezing, angioneurotic
edema, serum sickness and exfoliative dermatitis are less common. Anaphylaxis
is rare ( I to 4 per l 0,000 patients), but may be fatal.
Supermfections These are rare with PnG because: of its narrow spectrum;
though bowel, respiratory and cutaneous micro flora undergo changes.

Jansch-Herxheimer reaction Penicillin injected in a syphilitic patient

(particularly secondary syphilis) may produce shivering. fever, myalgia,
exacerbation of lesions, even vascular collapse. This is due to sudden release
of spirochetal lytic products. It does not recur and does not need interruption
of therapy. Aspirin and sedation afford relief of symptoms.
 Cephalosporins
These are a group of semisynthetic antibiotics derived from 'cephalosporin-C
obtained from a fungus Cephalosporium. They are chemically related to penicillins;
the nucleus consists of a β-lactam ring fused to a dihydrothiazine ring, (7-
aminocephalosporanic acid).
All cephalosporins are bactericidal and have the same mechanism of action as
penicillin, i.e. inhibition of bacterial cell wall synthesis.
Uses
Currently cephalosporins are one of the most commonly used antibiotics. Among
them they cover a wide range of gram-positive and gram negative bacteria
including some anaerobes, but not B. fragilis, mycobacteria and chlamydia.

I. As alternatives to penicillins for ENT, upper respiratory and cutaneous infections,

one of the first generation compounds may be used.

2. Respiratory, urinary and soft tissue infections caused by gram-negative

organisms, especially Klebsiella, Proteus, Enterobacter Serratia. Cephalosporins
preferred for these infections are cefuroxime, cefotaxime, ceftriaxone.

3. Penicillinase producing staphylococcal infections. Complicated skin and soft

tissue infections due to MRSA can now be treated by ceftaroline fosamil.
4. Septicaemias caused by gram-negative organisms: an aminoglycoside may be
combined with a cephalosporin.

5. Surgical prophylaxis : the first generation cephalosporins are popular drugs.

Cefazolin (i.m. or i.v.) is employed for most types of surgeries including those
with surgical prosthesis such as artificial heart valves, artificial joints, etc.
6. Meningitis : Optimal therapy of pyogenic meningitis requires bactericidal activity
in the CSF, preferably with antibiotic concentrations several times higher than the
MBC for the infecting organism. Ceftazidime + gentamicin is the most effective
therapy for Pseudomonas meningitis.

7. Gonorrhoea caused by penicillinase producing organisms: ceftriaxone is a first

choice drug for single dose therapy of gonorrhoea

8. Typhoid: Currently, ceftriaxone and cefoperazone injected i.v. are the fastest
acting and most re liable drugs for enteric fever.

9. Mixed aerobic-anaerobic infections in cancer patients, those undergoing

colorectal surgery, obstetric complications: cefuroxime, cefaclor or one of the
third generation compounds is used.

10. Hospital acquired infections, especially respiratory and other infections in

intensive care units, resistant to commonly used antibiotics. Cefotaxime,
ceftizoxime or a fourth generation cephalospo1in may be combined with
vancomycin.
Adverse Effects
Cephalosporins have low toxicity and are generally safe. The most common adverse
reactions from cephalosporins are nausea, vomiting, lack of appetite, and
abdominal pain.
The less common adverse reaction includes:

1.Hypersensitivity Reaction
Common allergic reaction to cephalosporin includes rash, hives, and swelling. 

2.Drug-induce Immune Hemolytic Anemia (DIIHA)

The proposed mechanism of action of DIIHA is that the drug binds to the red
blood cell membrane; this causes no harm to the red blood cell itself nor the
patient. However, if the patient starts making IgG antibodies against the drug,
the antibody will bind the red blood cell. The immune system will react with the
abnormal red blood cell resulting in hemolysis. E.g. Cefotetan and ceftriaxone

3.Disulfiram-like Reaction 
Cephalosporins containing a methyltetrazolethiol side chain can inhibit the
aldehyde dehydrogenase enzyme resulting in the accumulation of acetaldehyde.
E.g. Cefamandole, cefoperazone, and moxalactam
4. Vitamin K Deficiency 
Certain cephalosporins can inhibit vitamin K epoxide reductase, preventing the
production of the reduced(active) vitamin K. Therefore, there is a decreased synthesis
of coagulation factors, and the patient is predisposed to hypoprothrombinemia.

5. Increase Nephrotoxicity of Aminoglycosides 

6. Pseudomembranous Colitis
swelling or inflammation of the large intestine (colon) due to an overgrowth of
Clostridioides difficile (C. difficile) bacteria. Pseudomembranous colitis is often
associated with the use of clindamycin and ampicillin. Cephalosporin use is also a
common cause of pseudomembranous colitis, especially third-generation
cephalosporins.